Studies Directed toward the Design of Orally Active Renin Inhibitors. 2. Development of the Efficacious, Bioavailable Renin Inhibitor (2S)-2-Benzyl-3-[[(1-methylpiperazin-4-yl)sulfonyl]propionyl]-3-thiazol-4-yl-L-alanine Amide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (A-72517)

Journal of Medicinal Chemistry

Volumn 36, Issue 4, 1993, Pages 460-467

  Rosenberg, Saul H ^a   Spina, Kenneth P ^a   Condon, Stephen L ^a   Polakowski, Jim ^a   Yao, Zhengli ^a   Kovar, Peter ^a   Stein, Herman H ^a   Cohen, Jerome ^a   Barlow, Jennifer L ^a   Klinghofer, Vered ^a   Egan, David A ^a   Tricarico, Karen A ^a   Perun, Thomas J ^a   Baker, William R ^a   Kleinert, Hollis D ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

N [2 BENZYL 3 [(1 METHYL 4 PIPERAZINYL)SULFONYL]PROPIONYL] 3 (4 THIAZOLYL)ALANINE N (1 CYCLOHEXYLMETHYL 2,3 DIHYDROXY 5 METHYLHEXYL)AMIDE; RENIN INHIBITOR; SULFONAMIDE; UNCLASSIFIED DRUG; ZANKIREN;

ANIMAL EXPERIMENT; ARTICLE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG ELIMINATION; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; FERRET; INTRAVENOUS DRUG ADMINISTRATION; MONKEY; NONHUMAN; PRIORITY JOURNAL; RAT;

ANIMAL; BLOOD PRESSURE; COMPARATIVE STUDY; DOSE-RESPONSE RELATIONSHIP, DRUG; DUODENUM; FERRETS; HAPLORHINI; HUMAN; INTESTINAL ABSORPTION; LIVER; MOLECULAR STRUCTURE; PIPERAZINES; RATS; RENIN; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 0027535899     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm00056a006     Document Type: Article

References (16)

1. Rosenberg, S. H.; Spina, K. P.; Woods, K. W.; Polakowski, J.; Martin, D. L.; Yao, Z.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Egan, D. A.; Tricarico, K. A.; Baker, W. R.; Kleinert, H. D. Studies Directed toward the Design of Orally Active Renin Inhibitors 1. Some Factors Influencing the Absorption of Small Peptides. J. Med. Chem., previous article in this issue.
2. Kleinert, H. D.; Luly, J. R.; Bopp, B. A.; Verburg, K. M.; Hoyos, P. A.; Karol, M. D.; Plattner, J. J.; Luther, R. R.; Stein, H. H. Profile of the Renin Inhibitor, Enalkiren (ABBOTT-64662). Cardiovasc. Drug Rev. 1990, 8, 203–219.
3. 2O oxidation afforded an intermediate sulfonyl chloride that was coupled with N-methylpiperazine: Rosenberg, S. H.; Denissen, J. F. Renin Inhibitors. European Patent Application 0 456 185, 1991.
4. Mazdiyasni, H.; Konopacki, D.; Dickman, D. A.; Zydowsky, T. M. Enzyme-Catalyzed Synthesis of Optically Pure β-Sulfonamidopropionic Acids. Useful Starting Materials for P-3 Site Modified Renin Inhibitors. Tetrahedron Lett. 1992, 34, 435–438.
5. Rosenberg, S. H.; Woods, K. W.; Sham, H. L.; Kleinert, H. D.; Martin, D. L.; Stein, H.; Cohen, J.; Egan, D. A.; Bopp, B.; Merits, I.; Garren, K. W.; Hoffman, D. J.; Plattner, J. J. Water Soluble Renin Inhibitors: Design of a Subnanomolar Inhibitor with a Prolonged Duration of Action. J. Med. Chem. 1990, 33, 1962–1969.
6. Rosenberg, S. H.; Woods, K. W.; Kleinert, H. D.; Stein, H.; Nellans, H. N.; Hoffman, D. J.; Spanton, S. G.; Pyter, R. A.; Cohen, J.; Egan, D. A.; Plattner, J. J.; Perun, T. J. Azido-Glycols: Potent, Low Molecular Weight Renin Inhibitors Containing an Unusual Post Scissile Site Residue. J. Med. Chem. 1989, 32, 1371–1378.
7. Bühlmayer, P.; Caselli, A.; Fuhrer, W.; Göschke, R.; Rasetti, V.; Rüeger, H.; Stanton, J. L.; Criscione, L.; Wood, J. W. Synthesis and Biological Activity of Some Transition-State Inhibitors of Human Renin. J. Med. Chem. 1988, 31, 1839–1846.
8. Kleinert, H. D.; Rosenberg, S. H.; Baker, W. R.; Stein, H. H.; Klinghofer, V.; Barlow, J.; Spina, K.; Polakowski, J.; Kovar, P.; Cohen, J.; Denissen, J. The Discovery of a Peptide-Based Renin Inhibitor with Oral Bioavailability and Efficacy. Science 1992, 257, 1940–1943.
9. Kleinert, H. D.; Baker, W. R.; Stein, H. H. Renin Inhibitors. Adv. Pharmacol. 1991,22, 207–250.
10. Blaine, E. H.; Schorn, T. W.; Boger, J. Statine-Containing Renin Inhibitor: Dissociation of Blood Pressure Lowering and Renin Inhibition in Sodium-Deficient Dogs. Hypertension 1984, 6 (suppl I), I-111–I-118.
11. Fischli, W.; Clozel, J.-P.; Amrani, K. E.; Wostl, W.; Neidhart, W.; Stadler, H.; Branca, Q. Ro 42-5892 Is a Potent Orally Active Renin Inhibitor in Primates. Hypertension 1991, 18, 22–31.
12. Plattner, J. J.; Marcotte, P. A.; Kleinert, H. D.; Stein, H. H.; Greer, J.; Bolis, G.; Fung, A. K. L.; Bopp, B. A.; Luly, J. R.; Sham, H. L.; Kempf, D. J.; Rosenberg, S. H.; Deilaria, J. F.; De, B.; Merits, I.; Perun, T. J. Renin Inhibitors. Dipeptide Analogues of Angiotensinogen Utilizing a Structurally Modified Phenylalanine Residue To Impart Proteolytic Stability. J. Med. Chem. 1988, 31, 2277–2288.
13. Anderson, A. G., Jr.; Lok, R. The Synthesis of Azetidine-3-carboxylic Acid. J. Org. Chem. 1972, 37, 3953–3955.
14. Mannich, C.; Ganz, E. Über β-Amino-dicarbonsäuren und Amino-polycarbonsäuren. Chem. Ber. 1922, 55, 3486–3504.
15. Martin, S. F.; Austin, R. E.; Oalmann, C. J.; Baker, W. R.; Condon, S. L.; de Lara, E.; Rosenberg, S. H.; Spina, K. P.; Stein, H. H.; Cohen, J.; Kleinert, H. D. 1,2,3-Trisubstituted Cyclopropanes as Conformationally Restricted Dipeptide Isosteres: Applications to the Design and Synthesis of Novel Renin Inhibitors. J. Med. Chem. 1992, 35, 1710–1721.
16. Preibisz, J. J.; Sealey, J. E.; Aceto, R. M.; Laragh, J. H. Plasma Renin Activity Measurements: An Update. Cardiovasc. Rev. Rep. 1982, 3, 787–804.